Brett Spear, PhD
ConnectOffice: (859) 257-5167
- MD/PhD Program Mentor
- Nutritional Sciences Graduate Faculty
- Toxicology - Joint Faculty
Biography and Education
B.S./B.A.: Biology/Chemistry; Southampton College of Long Island University (1976-1980) Ph.D.: Immunology; University of Pennsylvania (Darcy Wilson, advisor; 1981-1985) Postdoc: Molecular Biology; Princeton University (Shirley Tilghman, advisor; 1986-1989)
The liver is the largest internal organ and carries out numerous functions that are essential to maintain homeostasis in vertebrates. Most of these functions are carried out by hepatocytes, which comprise 80% of liver mass, but other cells, including Kupffer cells and stellate cells, are essential for normal liver function. The liver has a defined lobular architecture that is functionally important. Hepatocytes in periportal and pericentral regions perform different metabolic functions, a phenomenon called liver zonation.The ability of the liver to carry out these functions require the exquisite and coordinated regulation of numerous hepatic genes.
Our research interests are in the area of gene regulation; in particular, we are interested in transcriptional regulation in the liver during development and disease. This began with analyzing regulation of the alpha-fetoprotein (AFP) gene, which is expressed abundantly in the fetal liver, silenced at birth, and reactivated during liver regeneration and liver cancer. This work has progressed in two different areas, both of which emphasize the use of mouse models but also include tissue culture, biochemical approaches and bioinformatics. The first focus is on the transcriptional basis of zonal regulation in the adult liver, which involves the interplay of different transcription factors, including TCF and RORa, and the Wnt/beta-catenin signaling pathways. The second focus is on a transcription factor called Zinc fingers and homeoboxes 2 (Zhx2), which we discovered, in collaboration with the lab of Dr. Martha Peterson, as an important regulator of liver gene expression. We are currently interested in the role of Zhx2 in lipid homeostasis, liver function in response to injury, developmental and sex-biased gene expression and hepatocellular carcinoma. We are also interested in the evolution of Zhx2 and related genes.
Dr. Spear also co-leads an NIH-funded program that provides grant writing and student mentoring training for faculty at minority-serving institutions. This training is provided through on-site and off-site workshops. More information about this program can be found at: https://research.med.uky.edu/research-imers.
NIH/NIDDK R01DK074816-14: “RORalpha and Hepatic Zonal Regulation” 09/2007- 06/2022.
NIH/NIGMS R25GM125680-02: “Interactive Mentoring to Enhance Research Skills (IMERS)” 09/2018-08/2023.
Nail, A.N., J. J. Smith, M.L. Peterson and B.T. Spear. (2020). Evolutionary analysis of the Zinc Finger and Homeoboxes family of proteins identifies multiple conserved domains and a common early chordate ancestor. Genome Biology and Evolution. 12(3):174-184. https://pubmed.ncbi.nlm.nih.gov/32125369/ Zhang, W., V.M. Sviripa, L.M. Kril, T. Yu, Y. Xie, W.B. Hubbard, P.G. Sullivan, X. Chen, C-G. Zhan, Y. Yang- Hartwich, B.M. Evers, B.T. Spear, R. Gedaly, D.S. Watt and C. Liu. (2019). An underlying mechanism of dual Wnt inhibition and AMPK activation: Mitochondrial uncouplers masquerading as Wnt inhibitors. J. Medicinal Chemistry. 62(24):11348-11358. https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01685 Clinkenbeard, E.L., C. Turpin, J. Jiang, M.L, Peterson and B.T. Spear. (2019). Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high fat diet are due, in part, to Zhx2. Mammalian Genome, 30(7-8):226-236. https://link.springer.com/article/10.1007/s00335-019-09811-6 Jiang, J, K.T. Creasy, J. Purnell, M.L. Peterson, B.T. Spear (2017) Zinc fingers and homeoboxes 2 (Zhx2) regulates Major Urinary Protein gene expression in the mouse liver. J. Biol. Chem. 292:6765-6774. https://www.jbc.org/content/292/16/6765.long Creasy, K.T., J. Jiang, H. Ren, M.L. Peterson, B.T. Spear (2016) Zinc fingers and homeoboxes 2 (Zhx2) regulates sexually dimorphic Cyp gene expression in the adult mouse liver. Gene Expression 17:7-17. https://www.ingentaconnect.com/content/cog/ge/2016/00000017/00000001/ar… Gedaly, R., R. Galuppo, M.F. Daily, M. Shah, E. Maynard, G. Chen, X. Zhang, D.A. Cohen, B.M. Evers, J. Jiang, and B.T. Spear. 2014. Targeting the Wnt/beta-catenin signaling pathway in Liver and Stem Cells and Hepatocellular Carcinoma Cell Lines with FH535. PLoS One, 9(6)e99272. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.00992… Clinkenbeard, E.L., J.E. Butler and B.T. Spear. 2012. Pericentral activity of AFP enhancer E3 and glutamine synthetase upstream enhancer in the adult liver are regulated by -catenin. Hepatology 56:1892-1901. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.25819 Peterson, M., C. Ma, and B.T. Spear. 2011. Zhx2 and Zbtb20, novel regulators of postnatal alpha-fetoprotein expression and their potential role in gene reactivation during liver cancer. Seminars in Cancer Biology. 21:21-27. https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S1044579X1100… Gargalovic, P.S., A. Erbilgin, O. Kohanim, J. Pagnon, X. Wang, L. Castellani, R. LeBeouf, M.L,Peterson, B.T. Spear and A.J. Lusis. 2010. Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Cir. Cardiovasc. Genetics. 3:60-67. https://www.ahajournals.org/doi/full/10.1161/CIRCGENETICS.109.902320?ur… Green, M.A., S. Bass and B. Spear. 2009. A device for the simple and rapid transcervical transfer of mouse embryos eliminates the need for surgery and potential post-operative complications. Biotechniques, 47:919-924. https://www.future-science.com/doi/10.2144/000113257?url_ver=Z39.88-200…; Perincheri, S., D.K. Peyton, M. Glenn, M.L. Peterson, and B.T. Spear. 2008. Characterization of the ETnII-endogenous retroviral element in the BALB/cJ Zhx2Afr1 allele. Mammalian Genome. 19:26-31. https://link.springer.com/article/10.1007%2Fs00335-007-9077-6 Morford, L.A., C. Davis, L. Jin, A. Dobierzewska, M.L. Peterson, and B.T. Spear. 2007. The oncofetal gene Glypican 3 is regulated in the postnatal liver by Zinc Fingers and Homeoboxes Protein 2 and in the regenerating liver by Alpha-fetoprotein regulator 2. Hepatology, 46:1541-1547. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.21825 Spear, B.T., L. Jin, S. Ramaswamy, and A. Dobierzewska. 2006. Transcriptional control in the mammalian liver: Liver development, perinatal repression, and zonal gene regulation. Cellular and Molecular Life Sciences 63:2922-2938. https://link.springer.com/article/10.1007%2Fs00018-006-6258-5 Perincheri, S., R.W.C. Dingle, M.L. Peterson and B.T. Spear. 2005. Hereditary persistence of alpha-fetoprotein and H19 expression in BALB/cJ mouse liver is caused by a hypomorphic mutation in the zinc-fingers and homeoboxes gene, Zhx2. Proc.Natl.Acad.Sci., USA, 102:396-401. https://www.pnas.org/content/102/2/396.long Seipelt, R. L., B.T. Spear, E.C. Snow, and M.L. Peterson. 1998. A non-Ig transgene and the endogenous Ig gene are coordinately regulated by alternative mRNA processing during B cell maturation. Molec. and Cell. Biol., 18(2): 1042-1048. https://mcb.asm.org/content/18/2/1042.long Ramesh, T., A.W. Ellis, and B.T. Spear. 1995. Individual mouse AFP enhancer elements exhibit different patterns of tissue specific and hepatic position-dependent activity. Molec. Cell. Biol., 15(9): 4947-4955. https://mcb.asm.org/content/15/9/4947.long Spear, B.T., and S.M. Tilghman. 1990. Role of alpha-fetoprotein regulatory elements in transcriptional activation in transient heterokaryons. Molec. and Cell. Biol. 10:5047-5054. https://mcb.asm.org/content/10/10/5047.long For a full list of publications, see https://www.ncbi.nlm.nih.gov/myncbi/1zGdknHeCr6Am/bibliography/public/